Deciphering Sequence‑Specific Rules Governing α‑Helical Peptide Oligomerization through electrostatic interactions and hydrophobic effect

De novo designed α‑helical peptides bearing non‑canonical NBD chromophores enable control of supramolecular assembly through defined interactions. Our first‑generation sequences formed monomers to tetramers through the clustering of hydrophobic moieties, with oligomer distributions dictated by linker length. Using these insights, we redesigned zwitterionic peptide variants that introduce specific lateral interactions that further modulate oligomer topology. Preliminary data now reveal fully discrete oligomers, instead of co-existing species, which can form higher-order oligomer through sequence manipulation. To resolve their structures and establish the sequence‑encoded rules governing hierarchical assembly, mesoscopic characterisation is essential. We propose SAXS experiments, integrated with MD, to correlate peptide sequence with oligomeric architecture and develop a general framework for rationally control peptide oligomerization.